(2024) 22:330
Pregernig et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03552-3

BMC Medicine

RESEARCH ARTICLE

Open Access

Vitamin B12 status and the riskof developing sepsis in patients with bacterial
infection: a prospective observational cohort
study
Andreas Pregernig1, Ulrike Held2, Martin Schläpfer1 and Beatrice Beck‑Schimmer1*

Abstract
Background Data have shown that vitamin B12 has immunomodulatory effects via different pathways, which could
influence the pathophysiology of sepsis. The objective of this study was to investigate whether vitamin B12 levels, assessedby the measurement of holotranscobalamin (HTC), total vitamin B12 (B12), and methylmalonic acid (MMA, which accumu‑
lates in case of B12 deficiency), are associated with the development of sepsis in patients with onset of bacterial infection.
Methods This was a single-center, prospective observational pilot study. Adult patients who presented to the emer‑
gency department with bacterial infection confirmed by a positive microbiological culture result were includedin the study and followed up for 6 days to assess whether they developed sepsis or not. The primary objective
was to compare HTC concentration in patients who developed sepsis to those who did not develop sepsis. Second‑ary objectives were the evaluation of B12 and MMA concentrations in those two groups. Multiple logistic regression
models were used, with presence of sepsis as the outcome variable, and HTC, B12, and MMA concentrations as pre‑dictor variables, separately, and adjusted for potential confounders.
Results From 2019 to 2022, 2131 patients were assessed for eligibility, of whom 100 met the inclusion criteria. One patientwas excluded from the analysis due to missing data. Of the 99 patients, 29 developed sepsis. There was no evidence
for an association between HTC or B12 concentration and the development of sepsis (OR 0.65, 95% CI 0.31–1.29, p = 0.232,
OR 0.84, 95% CI 0.44–1.54, p = 0.584, respectively). There was an association between MMA concentration and the devel‑
opment of sepsis, with a positive effect, i.e. with increasing MMA, the odds for sepsis increased (OR 2.36, 95% CI 1.21–4.87,
p = 0.014). This association remained significant when adjusted for confounders (OR 2.72, 95% CI 1.23–6.60, p = 0.018).
Conclusions Our study found an association between elevated MMA concentration and the development of sepsis.
We did not find an association between HTC and B12 concentrations and the development of sepsis. Further, larger
studies are warranted, as it could lead to interventional trials investigating whether B12 supplementation provides
a clinical benefit to patients with infection or sepsis.
Trial registration The study was registered on ClinicalTrials.gov under the identifier NCT04008446 on June 17, 2019.
Keywords Sepsis, Infection, Vitamin B12, Holotranscobalamin, Methylmalonic acid, Prospective, Observational study*Correspondence:
Beatrice Beck‑Schimmer
beatrice.beckschimmer@uzh.ch; beatrice.beck@usz.ch
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.

Pregernig et al. BMC Medicine(2024) 22:330

Background
Sepsis affects millions of people throughout the world[1]. To this day, it is still one of the main causes of deathin intensive care units (ICUs), with high mortality rates
across all countries [2, 3]. Sepsis pathophysiology is characterized in part by excessive generation of potent proinflammatory cytokines and chemokines, reactive oxygen
species, and nitric oxide (NO), as well as redox imbalance
and widespread immunothrombosis which can result indisseminated intravascular coagulation [4, 5].
Malnutrition is well known to interfere with the
immune system and constitute a risk factor for infection[6, 7]. But there is also increasing evidence that deficiency
or marginal deficiency in micronutrients (vitamins andtrace elements) is linked with an altered immune function and susceptibility to infection or sepsis [8–10].
Vitamin B12 (cobalamin) is a water-soluble vitaminthat is obtained from animal dietary sources. Three quarters of vitamin B12 circulate in the blood bound to haptocorrin, and one quarter is bound to transcobalamin
to form holotranscobalamin (HTC), the physiologically
active form of B12 presented for cellular uptake [11].
In the cell, B12 is required by two enzymes [12]: methylmanolyl-CoA mutase which converts methlymalonic acid
(MMA) to succinyl-CoA, an intermediary in the Krebs
cycle, and methionine synthase which converts homocysteine to methionine, which is essential for protein synthesis and is involved in cellular methylation reactions (e.g.,
methylation of DNA, histones and other regulators of gene
expression). Total vitamin B12, HTC, as well as MMA andhomocysteine, which accumulate in case of B12 deficiency,
can be measured in the blood to determine vitamin B12
status, although homocysteine has low specificity for thisuse as other causes can lead to its accumulation [11].
Vitamin B12 deficiency is frequent and occurs in 6% of
people under 60 years, and 20% in people over 60 [13, 14].
Marginal or subclinical deficiency is even more common,but its clinical relevance is still unknown [15–17]. Whilevitamin B12 deficiency is mainly known for its hematological and neurological manifestations, some data havesuggested a link between vitamin B12 and inflammation.
Cobalamin has notably been shown to act as an antioxidant, suppress cytokine production, and regulate NO
synthase activity [18–20]. A study also demonstrated thatvitamin B12 deficiency increases tumor necrosis factoralpha and lowers epidermal growth factor in cerebrospinal fluid and serum [21]. In patients suffering fromsepsis, methionine metabolites and homocysteine (bothlinked to vitamin B12) have been shown to be abnormal[22, 23]. An animal model further indicated that low vitamin B12 levels are correlated with susceptibility to an
infectious challenge [24]. Data regarding human subjects
are still scarce.

Page 2 of 10

Vitamin B12 deficiency is relevant today and may
increase in the near future due to vegetarianism, veganism, the use of proton pump inhibitors or metformin,
gastro-intestinal surgery, and an overall aging population[13, 25, 26]. An association between low vitamin B12 status and the occurrence of sepsis could lead to interventions aiming to increase vitamin B12 levels thus lowering
the risk of sepsis in patients with infection.
In this study, we assessed if vitamin B12 levels, determined by the measurement of HTC, vitamin B12, andMMA, were associated with the development of sepsis,in patients admitted to the emergency department (ED)with onset of microbiologically confirmed bacterial infection. The hypothesis is that patients with positive culturesdeveloping sepsis have lower vitamin B12 levels thanthose who do not develop sepsis.

Methods
This was a single-center prospective observational cohort
study which took place at the University Hospital Zurich(Zurich, Switzerland). It was approved by the local ethics committee (KEK ZH 2019 number 00702) and was
registered on ClinicalTrials.gov under the identifier
NCT04008446 on June 17, 2019.
Study participants

Adult patients (≥ 18 years old) presenting to the EDwith fever (≥ 38 °C) and a quick Sequential Organ Failure Assessment score (qSOFA) of ≤ 1 who had a positive
microbiological culture result were included in the study.
Pregnant or breastfeeding patients, and patients unable to provide informed consent were excluded from thestudy.
Study design

As there are few data about vitamin B12 status inpatients with sepsis, this was a pilot study. On weekdays (Monday to Friday), consecutive patients who
were admitted to the ED with suspicion of infection were screened, and those with fever (≥ 38 °C),
qSOFA ≤ 1, and for whom microbiological cultures
were ordered or sampled were prospectively enrolled.
A member of the study team asked the patients fortheir written consent for sampling of one blood vial
and participation in the study. If consent was obtained,
one blood sample was obtained in the ED. This blood
sample was centrifuged, and the serum aliquot wasstored pending the results of the microbiological cultures. If at least one of the culture results was positive
for bacterial infection, the patient was included in the
study and the serum was analyzed. If all cultures were
negative, the serum was discarded and the patient was
not included in the study. Patients were followed for 6

Pregernig et al. BMC Medicine(2024) 22:330

consecutive days after ED admission to assess whether
they developed sepsis or not. After 6 days, they were
either stratified as bacterial infection with sepsis orbacterial infection without sepsis. Sepsis was definedaccording to the Sepsis-3 definitions [27].
Determination of HTC, B12, and MMA plasma
concentrations

One blood sample (red BD Vacutainer® Clot Activator
Tube) was obtained in the ED by a member of the study
team. As soon as possible after allowing the blood toclot (20 to 30 min), the blood sample was centrifuged
and the serum aliquot was stored in a freezer at a temperature of − 20 °C and protected from light exposure.
For patients who had a positive microbiological culture,serum concentrations of HTC, B12, and MMA werethen determined by the Institute of Clinical Chemistry of the University Hospital Zurich. The assays used
for the measurements were Active-B12 (with Architect
i200SR device, by Abbott) for HTC, Elecsys Vitamin
B12 II (with Cobas 8000 e801 Module, by Roche) for
B12, and MassChrom® Methylmalonic Acid (by Chromsystems, with 4500MD mass spectrometer by Sciex) for
MMA. All the assays used are commercial and successfully underwent external quality control and proficiency
testing.
Objectives and outcomes

The primary objective of our study was to compare the
HTC concentration in patients who developed sepsis tothose who did not develop sepsis. Secondary objectives
were the evaluation of vitamin B12 and MMA concentrations in those two groups.
Statistical analyses

The sample size was calculated to detect a difference in
HTC concentration with a predefined precision. A difference in HTC concentration with a 95% confidence
interval width of 20 pmol/l yielded a sample size of 100
patients.
For the results, multiple logistic regressions models
were used, with presence of sepsis as the binary outcome variable, and independent variables HTC, vitamin B12, and MMA concentrations, separately, andadjusted for potential confounders selected on the basisof clinical knowledge (malnutrition, defined as medium
or high risk of malnutrition according to MUST score[28], age, diabetes). Continuous data were presented asmean and standard deviation or median and interquartile range (IQR) if not normally distributed. Categorical
data were presented as numbers (n) and proportions(%) of total. Results were presented as odds ratios with
95% confidence intervals. In addition, thresholds toPage 3 of 10

define B12 deficiency vary between different countries
and centers [14], and while the study objective was tocompare HTC, B12, and MMA concentrations regardless of any threshold, we compared the proportion ofpatients with B12 deficiency and marginal deficiency
according to the latest published NICE guidelines [29].
The statistical programming language R, version 4.2.2,
was used for all statistical analyses [30]. The study was
performed in accordance with the Strengthening theReporting of Observational studies in Epidemiology(STROBE) guidelines (Additional file 1) [31].

Results
From June 2019 to November 2022, 2131 patients wereassessed for eligibility. 1830 patients did not meet theinclusion criteria. Of the remaining 301 patients, 44
declined participation in the study, 157 were excluded
due to negative microbiological culture results, and 100
were included in the study. One patient was excluded
from the analysis due to missing data (transfer to anotherhospital) that precluded formal adjudication of whether
he developed sepsis or not. The other 99 patients were all
included in the statistical analysis. A flow diagram of thestudy is shown in Fig. 1.
The patients’ baseline characteristics and relevantcomorbidities are shown in Table 1. The mean patientage was 59 years. Only 4 patients were receiving vitamin
B12 supplementation prior to ED admission. 20 patientswere deemed at high risk of malnutrition, with a Malnutrition Universal Screening tool (MUST) score of 2
points or more. The majority of patients had a genitourinary source of infection, and the second most frequent source of infection was intra-abdominal. Of the
99 patients included in the study, 29 developed sepsis.
The proportion of patients who had a qSOFA score of
1 at baseline was higher in the group of patients whodeveloped sepsis, but baseline characteristics between
patients who developed sepsis and those who did not
develop sepsis were balanced, with no other statisticallysignificant difference.
The median HTC concentration in patients whodeveloped sepsis was 61 pmol/l (IQR 44–93), and71 pmol/l (IQR 48–120) in patients who did not
develop sepsis (p = 0.319). B12 and MMA concentrations in the no-sepsis group compared to the sepsis
group were 421 ng/l (IQR 287–717) and 384 ng/l (IQR
250–701) (p = 0.541), and 150 nmol/l (IQR 102–224)
and 217 nmol/l (IQR 133–345) (p = 0.018), respectively. HTC, B12, and MMA values are depicted in
depicted in Fig. 2.
Multiple logistic regression models were fitted withsepsis as the outcome variable and either HTC, B12,or MMA as predictor variables. In the analysis, therePregernig et al. BMC Medicine(2024) 22:330

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Fig. 1 STROBE flow diagram

was no association between HTC or B12 concentration and sepsis. We did find an association between
MMA concentration and the development of sepsis,with a positive effect, i.e., with increasing MMA, theodds for sepsis increased. The models are summarizedin Table 2.
In addition, to control for potential confounding, thevariables age, diabetes, and malnutrition were includedin the aforementioned models. While there was still
no evidence for an association between HTC or B12
and sepsis, the association between MMA and sepsis
remained significant when confounders were includedin the logistic regression model. These models are presented in Table 3.
Finally, we compared the proportion of patientswith B12 deficiency and marginal deficiency according to the latest published NICE guidelines. The proportion of patients with B12 deficiency defined by
MMA ≥ 360 nmol/l (in patients 65 years old or more)or MMA ≥ 280 nmol/l (in patients 64 years old or less)was significantly higher in the group of patients withsepsis, compared to those who did not develop sepsis.
There was no significant difference when using thresholds of HTC < 25 pmol/l or B12 < 180 ng/l for deficiency, or HTC 25–70 pmol/l and B12 180–350 ng/l
for marginal deficiency. The results are detailed inTable 4.

Discussion
This study investigated whether vitamin B12 status,
assessed by the measurement of HTC, vitamin B12, andMMA, was associated with the development of sepsis inpatients who present to the ED with onset of bacterial
infection. The results of our study show an association
between elevated MMA concentration and the development of sepsis. This association remained significant
when potential confounders were included in the analysis. We did not find evidence for an association between
HTC or total vitamin B12 concentration and development of sepsis.
The role of micronutrients and vitamins in the pathophysiology of sepsis has been thoroughly researched inrecent years. A part of the appeal of these molecules
is their generally favorable safety profile when used asa treatment regimen, as well as their availability [32].
Some of the most rigorously researched micronutrients
include vitamin C, B1, and vitamin D. Early data supported that low vitamin C was associated with worse
outcome in sepsis, and that treatment with vitaminC, used in isolation or in combination with vitamin
B1 and other agents, might reduce organ damage andmortality in septic patients [33–35]. The latest studies are more conflicting, and the evidence for a clinical benefit remains unclear [36–40]. Similarly, vitamin
D deficiency was associated with increased susceptibility to infections and worse outcome in sepsis patients,

Pregernig et al. BMC Medicine(2024) 22:330

Page 5 of 10

Table 1 Patients baseline characteristics
All patients (n = 99)

No-sepsis (n = 70)

Sepsis (n = 29)

SMD

p*

Age (mean (SD))

58.60 (18.56)

57.26 (18.54)

61.83 (18.51)

0.247

0.267

Female (%)

46 (46.5)

36 (51.4)

10 (34.5)

0.347

0.188

Male (%)

53 (53.5)

34 (48.6)

19 (65.5)

Ethnicity (%)
Asian

3 (3.0)2 (2.9)1 (3.4)Black

3 (3.0)3 (4.3)0 (0.0)

Hispanic

2 (2.0)1 (1.4)1 (3.4)White

91 (91.9)

64 (91.4)

27 (93.1)

26 (26.3)

16 (22.9)

10 (34.5)

Received antibiotics before blood cultures sampled (%)
Obesity (%)

0.347

0.188

0.327

0.640

0.259

0.344

0.369

0.320

0.456

0.076

No

77 (77.8)

52 (74.3)

25 (86.2)

Yes

12 (12.1)

9 (12.9)

3 (10.3)NA

10 (10.1)

9 (12.9)

1 (3.4)

No89 (89.9)

66 (94.3)

23 (79.3)

Yes

7 (7.1)3 (4.3)4 (13.8)NA

3 (3.0)1 (1.4)2 (6.9)

Past transplantation (%)

20 (20.2)

15 (21.4)

5 (17.2)

0.106

0.844

Chronic kidney disease (%)

17 (17.2)

12 (17.1)

5 (17.2)

0.003

1

Smoking (%)

Diabetes (%)

19 (19.2)

15 (21.4)4 (13.8)

0.201

0.550

Cancer (%)

32 (32.3)

23 (32.9)9 (31.0)

0.039

1Liver disease (%)

13 (13.1)

6 (8.6)7 (24.1)

0.431

0.078

Pancreatic disease (%)

2 (2.0)2 (2.9)0 (0.0)

0.243

0.893

Medication
Vitamin B12 supplementation (%)

4 (4.0)2 (2.9)2 (6.9)

0.188

0.713

PPI or other antacids (%)

40 (40.4)

26 (37.1)

14 (48.3)

0.227

0.422

Metformin (%)

9 (9.1)8 (11.4)

1 (3.4)

0.308

0.383

Immune suppressors (%)

34 (34.3)

23 (32.9)

11 (37.9)

0.106

0.802

0.399

0.360

Low risk (0 pts)

54 (54.5)

42 (60.0)

12 (41.4)

Medium risk (1 pt)

7 (7.1)5 (7.1)2 (6.9)High risk (≥ 2 pts)

20 (20.2)

12 (17.1)

8 (27.6)NA

18 (18.2)

11 (15.7)

7 (24.1)

qSOFA score = 1 (%)

34 (34.3)

17 (24.3)

17 (58.6)

0.744

0.002

Risk of malnutrition according to MUST score (%)

Infection focus (one patient may have more than one focus)
Genito-urinary (%)

50 (50.5)

37 (52.9)

13 (44.8)

0.161

0.613

Intra-abdominal (%)

20 (20.2)

13 (18.6)

7 (24.1)

0.136

0.724

Pulmonary (%)

11 (11.1)

6 (8.6)5 (17.2)

0.261

0.369

Skin/soft tissue/catheter (%)

6 (6.1)4 (5.7)2 (6.9)0.049

1

Other (%)

4 (4.0)4 (5.7)0 (0.0)

0.348

0.451

Unknown (%)

11 (11.1)

8 (11.4)

3 (10.3)

0.035

1

n number, SMD standardized mean difference, p p-value, SD standard deviation, NA missing data, PPI proton pump inhibitor, MUST Malnutrition Universal Screening
Tool, qSOFA quick Sequential Organ Failure Assessment score*

Exploratory p-values

but randomized trials assessing vitamin D have shown
mixed results [41–44]. Vitamin B12 has been comparatively less investigated than other vitamin micronutrients, with scarce human data available, mostly

from retrospective sources, and no randomized trial
to this date, despite promising preclinical studies [45,46]. However, recently, a phase 2 pilot randomized
controlled trial evaluated high-dose intravenousPregernig et al. BMC Medicine(2024) 22:330

Page 6 of 10

Fig. 2 HTC, B12, and MMA concentrations, in patients stratified according to whether or not they developed sepsis

hydroxycobalamin as a treatment regimen in septic shock patients, with results showing that the conducting of larger phase-2 and phase-3 trials should befeasible, as well as promising clinical results (lower
vasopressor use in the group of patients treated with
B12, absence of serious adverse events) despite thesmall sample size, although these were not the main
outcomes of the study [47].
The strengths of our study are its prospective nature,and that we included patients at onset of bacterial
infection, when they first presented to the ED, allowing
us to take the blood samples as soon as they entered
the ED and thus very early in the development of disease, before administration of any fluids or other treatments which could interfere with the measurementof B12 status. For this reason, we excluded patients
who were overtly in septic shock (qSOFA > 1) and who

might have already received large quantities of fluids
in the pre-hospital setting. We also evaluated vitamin
B12 status not only through total vitamin B12 concentration but also with HTC and MMA concentrations,which allows a more precise assessment of vitamin B12
status [11].
Our study also has limitations. This being a pilot
study, the sample size is quite low. With very few clinical data available, we had to opt for a precision-based
sample size calculation rather than a power-based
calculation. Focusing on patients admitted to the ED
allowed us to include patients at the very beginning of
the onset of bacterial infection, but we did not recruit
patients who developed infections while hospitalized
in medical or surgical units, which could have also provided insightful data. We drew blood samples at admission to the ED before the results of microbiologicalPregernig et al. BMC Medicine(2024) 22:330

Page 7 of 10

Table 2 Results of the logistic regression models, unadjusted

CI confidence interval, p p-value

cultures were known, exclusively in patients who had
fever (≥ 38.0 °C). This ensured we only sampled bloodin patients who were highly likely to develop positive
cultures, thereby preventing the sampling and discarding of large amounts of blood samples which would be
unethical and logistically unfeasible due to the highnumber of patients. These inclusion criteria (presence of fever and microbiologically confirmed bacterial infection) entail that some patients could not be
included (such as patients with bacterial infection but
who presented to the ED without fever), which might
affect generalizability, but they were necessary to limit
the heterogeneity of the patient population, given that
this was a pilot study with a sample size of 100 patients.
We also showed that the proportion of patients with
B12 deficiency was higher in the group of patients whodeveloped sepsis when using MMA ≥ 360 nmol/l (inpatients 65 years old or more) or MMA ≥ 280 nmol/l(in patients 64 years old or less) as a threshold, butthese results should be interpreted with caution as
there was no difference when using thresholds basedon HTC or B12 concentration for deficiency or for
marginal deficiency, and this was not a main outcome
for which this study was powered. Our study was performed in Switzerland and most included patients areof white ethnicity. Some geographical regions, including Latin America, Asia, and Africa, have a muchhigher prevalence of B12 deficiency, sometimes as highas 80% [17], and investigating the association between
B12 deficiency and sepsis in such regions might provide different results. Prevalence of B12 deficiency
also varies according to ethnicity within a single geographical region, and studies have shown great variability between different ethnic groups within regions
such as the USA, UK, and New Zealand [48, 49]. Someauthors have even suggested the need for reference
intervals adjusted for specific ethnicities [50]. Having a
study population composed of over 90% of whites prevented ethnic heterogeneity from significantly affecting
the investigation of the association between B12 deficiency and sepsis, albeit at the cost of limited insight
into other ethnicities.
Sepsis is incredibly complex with numerous demographic, genetic, and clinical factors influencing its development and pathophysiological pathways [4]. The resultsof our pilot study are promising and could indicate thatvitamin B12 status might have an implication in thedevelopment of sepsis. Of the markers of B12 status, only
the difference in MMA was statistically significant. While
HTC and B12 concentrations were lower in the sepsis
group compared to the no-sepsis group, the differenceswere not significant. Larger prospective studies mightprovide enough power to detect a difference in absolute
B12 and HTC concentrations.

Pregernig et al. BMC Medicine(2024) 22:330

Table 3 Results of the logistic regression models, adjusted formalnutrition (defined as medium or high risk according to MUSTscore), age, and diabetes

CI confidence interval, p p-value

Page 8 of 10

In addition, not only outright deficiency but subclinical deficiency and functional deficiency might be a risk
factor for sepsis. Cutoff thresholds in B12 or HTC values to define deficiency vary between countries andhospitals. There is a range between deficiency and normal values, known as marginal deficiency, which is of
yet unknown clinical significance, and which could bea risk factor for sepsis [51]. Normal B12 or HTC values
also do not exclude deficiency. A technically normal
value may, depending on individual variability, be insufficient in a specific patient, as shown by the accumulation of MMA and homocysteine in the blood. MMA
has been described as the best marker for assessing B12
status, as it reflects the function of the vitamin and notjust its absolute concentration in the blood [15, 52]. The
measurement of MMA and evaluation of subclinical deficiency should be considered in the design of further studies investigating the association between B12 deficiency
and sepsis.

Conclusions
In conclusion, we performed a prospective observationalpilot study, assessing if vitamin B12 status is associatedwith the development of sepsis in patients with the onsetof bacterial infection. Our study found evidence of an
association between elevated MMA concentration andthe development of sepsis. We did not find an association
between HTC and B12 concentration and the development of sepsis. Our pilot study encourages further, larger
studies, precisely investigating if vitamin B12 deficiency
is associated with sepsis, including the measurement of
MMA and the evaluation of subclinical deficiency, as wellas the derivation of thresholds which could be used inclinical practice. If additional studies also find evidenceof this association, it could lead to interventional trials
investigating whether B12 supplementation provides aclinical benefit to patients with infection or sepsis.

Table 4 Proportion of patients with B12 deficiency and marginal deficiency according to the thresholds from the 2024 Vitamin B12
deficiency NICE guideline summary*According to Fisher’s exact test
†According to Pearson’s chi-squared test with Yates’ continuity correction

Pregernig et al. BMC Medicine(2024) 22:330

Abbreviations
95% CI	95% Confidence interval
B12	Total vitamin B12ED	Emergency department
HTC	Holotranscobalamin
ICU	Intensive care unit
IQR	Interquartile range
MMA	Methlymalonic acid
MUST	Malnutrition Universal Screening toolNO	Nitric oxide
OR	Odds ratioqSOFA	Quick Sequential Organ Failure Assessment score
SOFA	Sequential Organ Failure Assessment score
STROBE	Strengthening the Reporting of Observational studies in Epidemiolog

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03552-3.
Additional file 1. STROBE Statement—Checklist of items that should be
included in reports of cohort studies.
Acknowledgements
The authors would like to thank Ms. Sabine Kern (study nurse) for her help
with drafting of the study protocol, recruiting patients, and collecting of data.
Authors’ contributions
AP was involved in the conception and design of the study, recruitmentof patients, acquisition, analysis and interpretation of the data, writing themanuscript, and its revision prior to submission. UH was involved in theconception and design of the study, analysis and interpretation of the data,and in the revision of the manuscript prior to submission. MS was involvedin the conception and design of the study, interpretation of the data, and in
the revision of the manuscript prior to submission. BBS was involved in theconception and design of the study, interpretation of the data, and in therevision of the manuscript prior to submission. All authors read and approved
the final manuscript.
Funding
Institutional funding (University of Zurich; BBS).
Availability of data and materials
The datasets used and/or analyzed during the current study are available fromthe corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
The study was approved by the local ethics committee (Zürich Kantonale
Ethikkommission, KEK ZH 2019 number 00702). All patients included in the
study provided their written consent for participation in the study.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Institute of Anesthesiology, University Hospital Zurich, Rämistrasse 100,
Zurich CH‑8091, Switzerland. 2 Epidemiology, Biostatistics and Prevention Insti‑tute, University of Zurich, Hirschengraben 84, Zurich CH‑8001, Switzerland.
Received: 12 January 2024 Accepted: 1 August 2024

Page 9 of 10

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